Elsevier

Tetrahedron

Volume 63, Issue 33, 13 August 2007, Pages 7753-7808
Tetrahedron

Tetrahedron report number 806
Recent advances in the chemistry of α,β-unsaturated trifluoromethylketones

https://doi.org/10.1016/j.tet.2007.04.029Get rights and content

Introduction

The trifluoromethyl group, due to its unique stereoelectronic properties, is one of the most important substituents in organic chemistry. Because of the close Van-der-Waals radii (CF3=1.35 Å, CH3=1.29 Å), a compound containing a trifluoromethyl group is comparable with its methyl analog and this plays a very important role in drug–receptor interactions. The high electronegativity of the CF3 group (3.5 on the Pauling scale) results in a quite different electron-density distribution and significantly changes the reactivity of the molecule. The influence of the trifluoromethyl group on the physiological activity is usually concerned with the increasing lipophilicity, which this substituent is bringing to the active molecules. The improvement of their transport characteristics in vivo and also the durability of the C–F bond compared with the C–H bond (116 and 100 kcal/mol, respectively), which allows the avoidance of undesirable metabolic transformations should be taken into consideration. In this respect, the introduction of trifluoromethyl groups into bioactive molecules, especially in the positions responsible for their physiological profile, becomes a very important direction in pharmaceutical studies that stimulates work directed to elaboration of synthetic methodology for various compounds containing trifluoromethyl groups.

The existing methods for direct fluorination and trifluoromethylation of organic compounds do not always allow the introduction of a CF3 group in the required position of the molecule. As a result, a more flexible synthetic approach based on the application of simple and available fluorine-containing compounds is a good supplement for direct fluorination methods and is nowadays gaining importance.

α,β-Unsaturated trifluoromethylketones are readily available compounds. Their application in synthesis broadens the arsenal of existing building blocks and demonstrates the perspective and potential of this approach for the introduction of trifluoromethyl groups into compounds from different alicyclic, carbo- and heterocyclic classes.

The literature up to 1999 have been highlighted previously by members of our scientific group in two reviews1, 2 describing the synthesis of α,β-unsaturated trifluoromethylketones and their application in organic synthesis. In the present review, the publications in this area over last seven years are discussed.

Section snippets

Methods for synthesis of α,β-unsaturated trifluoromethylketones

Analysis of the literature shows that several basic methods for the synthesis of α,β-unsaturated trifluoromethylketones were at the center of various investigations and these can be classified starting from the structure of the target compounds 1.

  • ― Creation of C2–C3 bonds (e.g., trifluoroacylation of alkenes).

  • ― Creation of C3double bondC4 bonds (e.g., condensation of carbonyl compounds with 1,1,1-trifluoroacetone derivatives).

  • ― Creation of C4–R3 or C4–R2 bonds (e.g., nucleophilic substitution at the

Synthesis of acetylenic CF3-ketones

The range of methods for the preparation of acetylenic CF3-ketones is much narrow than that for the preparation of CF3-enones. There are only several universal methods for the preparation of acetylenic CF3-ketones. One of the classical methods is the trifluoroacylation reaction of anions generated from terminal alkynes under treatment with strong bases. This approach was used for the synthesis of conjugated acetylenic ketones 237 containing perfluorinated groups. Acetylenides generated from

Application of α,β-unsaturated trifluoromethylketones in synthesis

The most outstanding area of application of α,β-unsaturated trifluoromethylketones is the synthesis of heterocyclic compounds, mainly due to their extensive synthetic utility, resulting in a large amount of work devoted to this problem. Heterocyclic compounds containing a trifluoromethyl group are attractive targets for medicinal chemistry and the elaboration of new effective methods for their synthesis is therefore an urgent and important task.

Conclusions

Summarizing the facts given in this review, it might be concluded that elaboration of new of methods for the preparation of α,β-unsaturated trifluoromethylketones should be continued, although the trifluoroacylation of activated alkenes remains the most applicable method. The synthesis of some derivatives is hard and challenging work, but, nevertheless these compounds possess very high synthetic potential as molecular building blocks containing the trifluoromethyl group. α,β-Unsaturated

Sergey V. Druzhinin was born in Domodedovo (Moscow region, Russia) in 1980. He graduated from the Department of Chemistry of Moscow State University in 2003. In 2006, he received his Ph.D. degree in organic chemistry from the Department of Chemistry of Moscow State University where he worked under the direction of Professor Valentine G. Nenajdenko. He is currently a post-doctoral fellow in Professor Valentine G. Nenajdenko research group. His research interests include organic synthesis,

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    Sergey V. Druzhinin was born in Domodedovo (Moscow region, Russia) in 1980. He graduated from the Department of Chemistry of Moscow State University in 2003. In 2006, he received his Ph.D. degree in organic chemistry from the Department of Chemistry of Moscow State University where he worked under the direction of Professor Valentine G. Nenajdenko. He is currently a post-doctoral fellow in Professor Valentine G. Nenajdenko research group. His research interests include organic synthesis, focusing on heterocyclic and fluorine-containing compounds.

    Elizabeth S. Balenkova was born in Moscow in 1926. She graduated from Moscow State University in 1950 and then she was a postgraduate student of the Department of Chemistry of Moscow State University. She received her Ph.D. degree under the supervision of academician B. A. Kazansky in 1953 for the research concerning medium ring hydrocarbons. Since that, she has been working at Moscow State University as a senior researcher (1959) and full professor (1986). She was a supervisor of 27 postgraduate and 63 diploma works. Her research interests are in the area of organic synthesis, electrophilic addition reaction, chemistry of heterocyclic and sulfur compounds.

    Valentine G. Nenajdenko was born in 1967 in Ivanovo, Russia. He graduated from Moscow State University (Lomonosov) in 1991. He received his Ph.D. degree under the supervision of Professor E. S. Balenkova in 1994 researching the synthesis and application of unsaturated CF3-ketones. In 2000 he received Dr. of Chemistry degree concerning chemistry of sulfonium and iminium salts. In 2003, he became full Professor of Organic Chemistry at the Department of Chemistry of Moscow State University. The field of his scientific interest includes organic synthesis, asymmetric catalysis, chemistry of sulfur and fluorine-containing compounds, and chemistry of various heterocycles. He was a supervisor of nine postgraduate works. Valentine G. Nenajdenko is head of Scientific Committee and Jury of International Mendeleev Chemistry Olympiad. He was the winner of the Academiae Europeae Award in 1997, the Russian President Award in 1996, the Prize for the best scientific work at the Department of Chemistry of Moscow State University 2001, Shuvalov Award 2001, the Russian President Award in 2004, Russian Science Support Foundation in 2005.

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